Identification and Specificity Studies of Small-Molecule Ligands for SH3 Protein Domains
- 29 September 2004
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 47 (22) , 5405-5417
- https://doi.org/10.1021/jm049533z
Abstract
The Src Homology 3 (SH3) domains are small protein-protein interaction domains that bind proline-rich sequences and mediate a wide range of cell-signaling and other important biological processes. Since deregulated signaling pathways form the basis of many human diseases, the SH3 domains have been attractive targets for novel therapeutics. High-affinity ligands for SH3 domains have been designed; however, these have all been peptide-based and no examples of entirely nonpeptide SH3 ligands have previously been reported. Using the mouse Tec Kinase SH3 domain as a model system for structure-based ligand design, we have identified several simple heterocyclic compounds that selectively bind to the Tec SH3 domain. Using a combination of nuclear magnetic resonance chemical shift perturbation, structure-activity relationships, and site-directed mutagenesis, the binding of these compounds at the proline-rich peptide-binding site has been characterized. The most potent of these, 2-aminoquinoline, bound with Kd = 125 microM and was able to compete for binding with a proline-rich peptide. Synthesis of 6-substituted-2-aminoquinolines resulted in ligands with up to 6-fold improved affinity over 2-aminoquinoline and enhanced specificity for the Tec SH3 domain. Therefore, 2-aminoquinolines may potentially be useful for the development of high affinity small molecule ligands for SH3 domains.Keywords
This publication has 19 references indexed in Scilit:
- Synthetic Inhibitors of Proline-Rich Ligand-Mediated Protein-Protein Interaction: Potent Analogs of UCS15AChemistry & Biology, 2003
- UCS15A, a novel small molecule, SH3 domain-mediated protein–protein interaction blocking drugOncogene, 2002
- The Solution Structure and Intramolecular Associations of the Tec Kinase Src Homology 3 DomainPublished by Elsevier ,2002
- Exploring the Leucine-Proline Binding Pocket of the Src SH3 Domain Using Structure-Based, Split-Pool Synthesis and Affinity-Based SelectionJournal of the American Chemical Society, 1998
- Exploring the Specificity Pockets of Two Homologous SH3 Domains Using Structure-Based, Split-Pool Synthesis and Affinity-Based SelectionJournal of the American Chemical Society, 1998
- Solution structure and ligand-binding site of the SH3 domain of the p85α subunit of phosphatidylinositol 3-kinaseCell, 1993
- Carbon-hydrogen insertions in the reactions of Fischer carbene complexes with ketene acetalsJournal of the American Chemical Society, 1992
- A Simple New Synthetic Method for the Preparation of 2-AminoquinolinesSynthetic Communications, 1991
- Stereochemical studies on medicinal agents. 30. Investigation of 4-(3-hydroxyphenyl)-4-methylpipecolic acid as a conformationally restricted mimic of the tyrosyl residue of leucine-enkephalinamideJournal of Medicinal Chemistry, 1986
- Analogs of 3-amino-7-chloro-1,2,4-benzotriazine 1-oxide as antimalarial agentsJournal of Medicinal Chemistry, 1968